4-amino-2-styrylquinazoline compounds

ABSTRACT

2-(R4-C6H4-CH=CH-),4-(R2-N(-R3)-),R1-QUINAZOLINE   AND ACID ADDITION SALTS THEREOF, ARE USEFUL AS ANTI-INFLAMMATORY AGENTS.   NEW 4-AMINO-2-STYRYLQUINAZOLINE DERIVATIVES WHICH HAVE THE GENERAL FORMULA

Patented Aug. 21, 1973 3,753,981 4-AMINO-2-STYRYLQUINAZOLINE COMPOUNDS Hermann Breuer, Burgweinting, and Ernst Schulze,

Regensburg, Germany, assignors to E. R. Squibb & Sons, Inc., New York, N.Y.

No Drawing. Filed July 15, 1970, Ser. No. 55,252 Int. Cl. C09b 23/14 U.S. Cl. 260-240 D 10 Claims ABSTRACT OF THE DISCLOSURE New 4-amino-2-styry1quinazoline derivatives which have the general formula and acid addition salts thereof, are useful as anti-inflammatory agents.

SUMMARY OF THE INVENTION This invention relates to new 4-amino-2-styrylquinazoline derivatives, as well as acid addition salts thereof, useful as anti-inflammatory agents, which have the formula Qrr MECHQ R is hydrogen, halogen, lower alkyl or lower alkoxy; R and R each is hydrogen, lower alkyl or lower alkoxy; and in addition, each of the basic nitrogen groups and is a 5- to 7-membered nitrogen monocyclic heterocyclic radical of up to 18 atoms (exclusive of hydrogen).

The symbols have these meanings throughout this specification.

DETAILED DESCRIPTION OF THE INVENTION The halogens represented by the symbols include the four common halogens, but chlorine and bromine are preferred. The lower alkyl groups include straight or branched chain hydrocarbon groups of up to 7 carbon atoms like methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like, the first two being preferred. The lower alkylene groups are hydrocarbon groups of the same kind. The lower alkoxy and hydroxy-lower alkyl groups similarly include such alkyl groups linked to an oxygen atom or hydroxy group, respectively, e.g., methoxy, propoxy, ethoxy, isopropoxy, hydroxymethyl, hydroxyethyl and the like. The lower alkoxy-lower alkyl groups are made up of similar radicals. The (hydroxy)lower alkylene groupincludes lower alkylene groups of the type referred to above in which one hydroxy group may be attached to any one of the carbons in the chain.

In the basic nitrogen containing radical in Formula I, R, and R each represents hydrogen, lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl forming such basic groups as amino, lower alkylamino, e.g., methylamino, ethylamino, isopropylamino, di(lower alkyl) amino, e.g., dimethylamino, diethylamino, dipropylamino, (hydroxy-lower alkyl)amino, e.g., hydroxyethylamino, di(hydroxy-lower alkyl)amino, e.g., di(hydroxyethyl)amino, (lower alkoxy-lower alkyl)amino, e.g., methoxymethylamino, Z-methoxyethylamino, or di(lower alkoxy-lower alkyl) amino, e.g., di(methoxymethyDamino, and the like.

In addition the nitrogen may join with the groups represented by R and R to form a 5 to 7 membered monocyclic heterocyclic containing, if desired, an oxygen, sulfur or an additional nitrogen atom, (not more than two hereto atoms althogether), e.g., piperidino, pyrrolidino, morpholino, thiamorpholino, piperazino, hexamethyleneimino and homopiperazino radicals. These heterocyclic groups may also be substituted by one or two groups lower alkyl, lower alkoxy, hydroxy-lower alkyl or alkanoyloxylower alkyl. The lower alkyl, lower alkoxy and hydroxylower alkyl groups are the same as those already described; the alkanoyl moieties are the acyl radicals of lower fatty acids, including for example, acetyl, propionyl, butyryl and the like, as well as acyl radicals of higher fatty acids of up to 14 carbons.

Heterocyclic groups represented by the radical II include for example, piperidino, di(lower alkyl)piperidino, e.g., 2,3-dimethylpiperidino, 2-, 3- or 4-(lower alkoxy)piperidino, e.g., Z-methoxypiperidino, 2-, 3- or 4-(lower alkyl) piperidino, e.g., 2-, 3- or 4-methylpiperidino, N-methylpiperidino, pyrrolidino, (lower alkyl)pyrrolidino, e.g., 2- methylpyrrolidino, di(lower alkyl)pyrrolidino, e.g., 2,3- dimethylpyrrolidino, (lower alkoxy)pyrrolidino, e.g., 2- ethoxypyrrolidino, N-lower alkylpyrrolidino, e.g., N- methylpyrrolidino, morpholino, (lower alkyl)morpholino, e.g., N-methylmorpholino or Z-methylmorpholino, di(lower alky1)morpholino, e.g., 2,3-dimethylmorpholino, (lower alkoxy)morp holi no, e.g., 2- e thoxymorpholino, thiamorpholino, (lower alkyl)thiamorpholino, e.g., N-methylthiamorpholino or 2-methylthiamorpholino, di(lower alkyl) thiamorpholino, e.g., 2,3- diethylthiamorpholino, 2,3-dimethylthiamorpholino, (lower alkoxy)thiamorpholino, e.g., Z-methoxythiamorpholino, piperazino, (lower alkyl) piperazino, e.g., 4-methylpiperazino, 2-methylpiperazino, (hydroxy-lower alkyl)piperazino, e.g., 4-(2-hydroxyethyl) piperazino, di(lower alkyl)piperazino, e.g., 2,3-dimethylpiperazino, alkanoyloxyflower alkyl)piperazino, e.g., N (2-dodecanoyloxyethyl)piperazino, hexamethyleneimino and homopiperazino.

Moreover, particularly when R; is hydrogen, R may be the basic group 5 lower alkylene-N v 7 R or such a group containing one hydroxy group on a carbon e.g., amino, lower alkylamino, di-lower alkoxyamino, as well as the same to fi-membered, unsubstituted and substituted nitrogen heterocyclics.

The compounds of Formula I form salts which are also part of this invention. The salts include acid-addition salts, particularly the non-toxic, physiologically acceptable members. The bases of Formula I form salts by reaction with a variety of inorganic and organic acids providing acid addition salts including, for example, hydrohalides (especially hydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate, succinate, benzenesulfonate, methanesulfonate, cyclohexanesulfamate, toluenesulfonate and the like. The acid addition salts frequently provide a convenient means for isolating the product, e.g., by forming and precipitating the salt in a medium in which the salt is insoluble, then after separation of the salt, neutralizing with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of Formula I. Other salts may then be formed from the free base by reaction with an equivalent of acid.

Preferred are those compounds of Formula I wherein R and R are both hydrogen or R is halogen, especially chlorine and R is hydrogen. Preferably also, R is hydrogen, especially when R is cli(lower alkyl)amino-lower alkylene, the lower alkylene particularly containing 5 carbons. Morpholino and 4-methylpiperazino are also preferred radicals. The hydrochlorides are preferred acid addition salts.

The new compounds of thisinvention have anti-inflammatory properties and are useful as anti-inflammatory agents, for example, to reduce local inflammatory conditions such as those of an edematous nature or resulting from proliferation of connective tissue in various mam malian species such as rats, dogs and the like when given orally in dosages of about 5 to S0 mg./kg./day, preferably 5 to 25 mg./kg./ day, in single or 2 to 4 divided doses, as indicated by the carageenan edema assay in rats. The active substance may be ntilzed in compositions such as tablets, capsules, solutions or suspensions containing up to about 300 mg. per unit of dosage of a compound or mixture of compounds of Formula I or physiologically acceptable acid addition salt thereof. They may be compounded in conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc. as called for by accepted pharmaceutical practice. Topical preparations containing about 0.01 to 3 percent by weight of active substance in a lotion, salve or cream may also be used.

The compounds of this invention are produced from 2-styryl-4-quinazolinones of the formula lCaCHQ which are treated with phosphorus oxychloride or equivalent halogenating agent in the presence of a tertiary amine like dimethylaniline and in an organic solvent like benzene, dimethylformamide or the like, preferably at an elevated temperature, to form new intermediates of the formula hal N R J The intermediate of Formula V is then made to react with an amine.

in a hydrocarbon solvent like benzene or toluene or in ether, dioxane, tetrahydrofuran or the like, preferably at an elevated temperature to obtain a product of Formula I.

The salts are formed as described above. The 2-styryl-4-quinazolones of Formula 1V may be produced by reacting a quinazolone of the formula (VII) I NH 1 N -CHa with an unsubstituted or substituted benzaldehyde (VIII) in the presence of a metal halide like zinc chloride (which is preferred) or aluminum chloride at a temperature of about to 200 C.

Alternatively an amide of the formula -ooNH,

may be reacted with a compound of the formula in an anhydrous solvent such as dioxane, tetrahydrofuran, or the like, in the presence of an acid binding agent such as pyridine, triethylamine or the like, to obtain a compound of the formula The compound of Formula XI is treated with a strong metal hydroxide like sodium or potassium hydroxide to eliminate water and produce a compound of Formula IV.

The following examples are illustrative of the invention and constitute preferred embodiments. Other members of the class may be similarly produced by varying the starting materials with the appropriately substituted analogs. All temperatures are on the centigrade scale.

The following examples are illustrative of the preparation of new intermediates of Formula V:

Example 1 A mixture of 28.3 gms. of 6-chloro-2-styryl-4(3H)- quinazolinone, 48.46 gms. (0.4 mol.) of dimethylaniline, 21.46 gms. (0.14 mol.) of phosphorous oxychloride and 350 ml. of benzene are refluxed with stirring for four hours. The solution is filtered while hot, and, after cooling to room temperature, is shaken with water. The benzene layer is separated, dried with calcium sulfate and concentrated. The residue crystallizes upon treatment with petroleum ether. The yield is 24.5 gms. of 4,6-dichloro-2- styryl quinazoline, M.P. 144145. The compound may be recrystallized from benzene, but is, however, pure enough for further conversion.

The following additional 4-chloro-2-styryl quinazolines are produced by the foregoing procedure from the appropriately substituted 2-styryl-4(3H)quinazolinone:

Melting oint deg.)

The following examples are illustrative of the preparation of new compounds of Formula I:

Example 10 8.4 gms. (0.028 mol.) of 4,7-dichloro-2-styrylquinazoline and 9.6 gms. of S-diethylamino-Z-pentylamine are refluxed with 90 ml. of benzene for 15 hours. The reaction mixture is cooled and the precipitated crystals of S-diethylamino-S-pentylamine hydrochloride are filtered under suction. The filtrate is concentrated and the residue is treated with 2 N sodium hydroxide solution. The organic phase is taken up in ether, the ether solution is dried With calcium sulfate, filtered and evaporated to dryness. The yield is 9.25 gms. of 7-chloro-4[[4-(diethylamino)- 1 methylbutyl1amino] Z-styrylquinazoline, M.P. 120- 122. The product is recrystallized from n-heptane.

6.6 gms. of the above product is dissolved in 50 ml. of isopropanol and treated with alcoholic hydrochloric acid until the pH is in the range of 2 to 3. The mixture is filtered under suction to obtain 7.8 gms. of 4-[[4-(diethy1 amino) l-methylbutyl]amino]-2-styrylquinazoline, dihydrochloride, M.P. 258261 (dec.).

The following additional compounds are obtained by the same procedure described above substituting the appropriate starting materials:

N Melting point (deg) Example R R4 R Base Salt 11 H H CH; CzH5 101-102 236-244 (2HOl) -NHC H (C H2) s-N 12.. G-Cl H Same as above 118-119 266-270 (2HOl) H 247-252 (lHCl) 4-Cl 286-288 (2HCl) 4-01 268-270 (2HCl-1/2Hz0 H 275-277 (2HC1) 4-Cl 284-285 (2HOl) H 1 250 (1.5HC1'0-5H20) 24- 7-OCH2 H CH: C2H5 85-89 '198-200 (2HC12HgO) -N Melting point (dag) Example R R; R; Base Salt H H (|)H 9H1 --NHCH2CHCH2N\ NHCH:CH:N N-C HzCHaOH 27..-.:.':.:'. H Z-OCH: CHzCHgOH --NH CHzC Hr-N CHzCHrOH NHCH2CH:N N

1 Dec.

Example 29 (lower alkyl) piperidino, pyrrolidino, (lower alkyl)pyr- 70 gms. of fi-methoxy 2 methyl-4(3H)-quinazo- 20 linone and 260 gms. of p-chloro'benzaldehyde are admixed and the mixture is placed on a bath preheated to 200. After a short time a clear melt results. 14 grns. of anhydrous zinc chloride are added and the resulting water is drawn off by water vacuum. After a short time the contents of the flask solidify. The mixture is added at 200 for an additional 15 minutes, then cooled, ethanol is added and then filtered under suction. The yield amounts to 111.7 gms. of 2-(p-chlorostyryl)-6-methoxy- 4(3H)-quinazolinone, M.P. 318-320".

Example 136.2 gms. of anthranilamide (1 mol.) are dissolved in 2 liters of dioxane. 71 gms. of pyridine are added and then 175 gms. (1.05 mol.) of cinnamoyl chloride are added all at once. The mixture is stirred for 30 minutes and then poured into 4 liters of water. After filtering under suction, washing with water and drying, there are obtained 260 gms. of 2'-carbamoylcinnamanilide, M.P. 233-237". This product is suspended in 12 liters of boiling water and sodium hydroxide is added to the suspension until a clear solution results. Upon the addition 013 glacial acetic acid, 2-styryl-4(3H)-quinazolinone precipitates which is filtered under suction, washed with hot water and then dried. The yield amounts to 238 gms., M.P. 248-252.

What is claimed is: 1. A compound of the formula CH=CH R4 wherein R; is hydrogen, halogen, nitro, lower alkyl or lower alkoxy; R is hydrogen, lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl; R is lower alkylene-N R is hydrogen, halogen, lower alkyl or lower alkoxy; R and R each is hydrogen, lower alkyl or lower alkoxy; and in addition the group is a member of the group consisting of piperidino, di-

(lower alkyUpiperidino, (lower alkoxy)piperidino,

rolidino, di(lower alkyl)pyrrolidino, (lower alkoxy) pyrrolidino, morpholino, (lower alkyl)morpholino, di-

(lower a1kyl)morpholino, (lower alkoxy)morpholino,

thiamorpholino, (lower aIkyDthiamorpholino, di(lower alkyl)thiamorpholino, (lower alkoxy)thiamorpholino,

piperazino, (lower alkyl)piperazino, (hydroxylower alkyl)piperazino, di(lower alkyl)piperazino, alkanoyloxy(lower alkyl)piperazino, hexamethyleneimino and homopiperaziuo; and acid addition salts thereof.

2. A compound as in claim 1 wherein R; and R each is hydrogen.

3. A compound as in claim 1 wherein R is halogen and R is hydrogen.

4. A compound as in claim 3 wherein the halogen is chlorine.

5. A compound as in claim 3 wherein R is hydrogen and R is di-lower alkylarnino-lower alkylene.

6. A compound as in claim 4 wherein R is hydrogen and R is (diethylamino) (methylbutyl)amino.

7. 7-chloro 2 (4 chlorostyryl) 4 [[4 (diethylamino) 1 methylbutyl]amino]quinazoline.

8. A compound of the formula lower alkyl NH-lower alkylene-N /\q ower alkyl R; J

CH=CH N wherein R is hydrogen, halogen, nitro, lower alkyl or lower alkoxy; and R is hydrogen, halogen, lower alkyl or lower alkoxy.

9. A compound as in claim 1 wherein R and R each is halogen.

10. A compound as in claim 9 wherein R is hydrogen.

References Cited UNITED STATES PATENTS 2,461,950 2/1949 Wolf 260-2564 Q 3,184,462 5/1965 Scarborough et a1.

260-2564 Q 3,301,855 1/1967 Blatter 260-2564 Q OTHER REFERENCES Serzhanina et al.: Zhur. Organ. Khim., vol. 7, pp. 1303-6 (1965) (translated version in English, pp. 1317- 1320 Kovendi et al.: Chem. Ber., vol. 98, pp. 1049 to 1059 (1965).

Dhatt, Current Science, vol. 30, pp. 179 to 180 (1961).

JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R. 424--246, 248, 251; 2605S8 A, 559 A 

